A number of clinical conditions involve (e.g., are caused by and/or themselves cause) impaired circulation, and particularly circulation within interstitial spaces and within discrete, localized tissues. Among the more vexing examples of such circulatory afflictions are those that involve localized tissue swelling, including compartment syndrome and edema (and in particular, cerebral edema).
Acute compartment syndrome generally involves impaired circulation within an enclosed fascial space (e.g., the anterior compartment of the lower leg), leading to increased tissue pressure and necrosis of muscle and nerves. The soft tissue of the lower leg is contained within four compartments, each bounded by heavy fascia—the anterior, lateral, superficial posterior, and deep posterior compartments. Once diagnosed, the injury requires immediate decompression through surgical release of the skin and fascia covering the area. Other proposed treatment strategies include the use of a sympathetic blockade, hyperbaric oxygen therapy, and treatment with mannitol and/or alloperinol.
Cerebral edema (also known as brain swelling), includes vasogenic cerebral edema (the most common form of edema) which manifests itself in the form of increased permeability of small vessels (breakdown of blood-brain barrier) and the escape of proteins and fluids into extracellular space, especially of white matter. Cerebral edema can be caused by ischemia, loss of oxygen, or focal disruption or loss of blood supply such as stroke. The diagnosis of cerebral edema is based on changes in mental status, imaging, and measurement of intracranial pressure. There remain few conventional treatment options, and they tend to be of limited efficacy.
Monitoring of intracranial pressure (ICP) is considered appropriate for all patients with severe traumatic brain injury (TBI). While the placement of an ICP monitor is invasive, the benefits of ICP monitoring are felt to offset this factor, carry a relatively small risk of complications (e.g., infection, hemorrhage, malfunction, obstruction or malposition), and rarely result in increased patient morbidity. Percutaneous devices (e.g., ventriculostomy catheters) for use in monitoring ICP are commercially available in a variety of styles and from a number of sources. Such devices are commonly placed within the cerebral ventricles, where they enable accurate and reliable monitoring of ventricular pressure and can be used for the therapeutic convective drainage of cerebrospinal fluid (“CSF”).CSF drainage has been described as a potentially effective method of lowering ICP, particularly when ventricular size has not been compromised. CSF drainage typically requires penetration of the brain parenchyma with a ventricular catheter. A variety of ventricular catheters are available for such purposes, e.g., the “MoniTorr” product available from Integra Lifesciences, Inc. As fluid is removed, however, brain swelling often progresses to the point where the ventricular system is compressed and the ability to drain CSF can be compromised. This may be exacerbated by overdrainage, leading to the ventricular walls or the choroid plexus actually collapsing in a manner that occludes the orifices of the catheter. The therapeutic efficacy of convective CSF drainage by conventional ventriculostomy catheters, therefore, has been limited to date.
On a separate subject, gases have long been used for various medical procedures. For instance, oxygen is generally used to enriched the atmosphere for patient therapy and procedures, though oxygen is considered a drug and is dispensed by prescription. High-pressure oxygen is used for hyperbaric treatment, while in other situations, medical air is inhaled by patients, often through secondary pneumatic equipment. Nitrous oxide provides the first and second stages of anesthesia, while nitrogen itself powers pneumatic surgical tools. Carbon dioxide gas is becoming more common in piped systems as it gains more use in advanced respiratory treatment and operating room procedures. Also helium, and mixtures of helium with oxygen, have been described for the treatment of patients having certain respiratory conditions.
An assortment of references also describe either the delivery or recovery of media, such as gases or hyperosmolar liquids, for various purposes and into various locations within the body. Such references include, for instance, situations in which oxygen is delivered to the body by means of catheters positioned within the blood, as well as those in which gases are themselves measured within bodily fluids. See, e.g., U.S. Pat. No. 4,274,417 (Instruments for use in the measurement of gases in body fluids); U.S. Pat. No. 4,726,381 (Dialysis system and method); U.S. Pat. No. 4,340,615 (Apparatus for analysis of absorbed gases); U.S. Pat. No. 5,865,789 (Percutaneous oxygenator for inducing a retrograde perfusion of oxygenated blood); U.S. Pat. No. 5,336,164 (Intravascular membrane lung apparatus); and U.S. Pat. No. 5,501,663 (Inflatable percutaneous oxygenator with transverse hollow fibers).
See also Levin, et al. U.S. Pat. No. 6,287,608, which describes a method and apparatus for the treatment of congestive heart failure by improving perfusion of the kidney by infusion of a vasodilator.
On yet another subject, medical-surgical vacuum and drainage systems exist in the art as well. For instance, the American Society for Testing and Materials provides standard specifications (F960-86(2000)) for medical and surgical suction and drainage systems that include applications such as oral, nasal and tracheal suction, gastrointestinal drainage, pleural space and mediastinal drainage, and closed wound drainage. Other examples, though not included within this specification, can include drainage by the use of catheters and similar instruments inserted into tissue sites, syringes, breast pumps, dentistry suction, and waste gas scavenging. See, for instance, the Mini VAC (Vacuum Assisted Closure) device, available from KCI (San Antonio, Tex.). The VAC device provides negative pressure therapy for the treatment of chronic and acute wound, and allows for the measurement and monitoring of therapy at the wound site through micro-processor control and multi-lumen tubing. In use, the negative pressure is applied to a special dressing positioned in a wound cavity or over a flap or graft. The pressure distributing wound dressing, in turn, is said to help remove fluids from the wound.
In a more recent approach, a “mechanical leech” has been developed, with the intent of attaching to a wound site in order to remove blood and promote wound heeling. See, for instance, the University of Wisconsin press release dated Dec. 12, 2001, “Novel Device Takes Over Where Medicinal Leeches Leave Off”.
See also U.S. Pat. No. 5,484,399, which describes a method and apparatus for reducing interstitial fluid pressure in tissues, particularly in tumors, by applying suction to the interior of the tissue. The method comprises inserting into the tissue one or more needle-like, elongated tubes, each having at least one hole at or near the end that is inserted into the tissue and each having means to apply suction to the protruding end. Components may be provided to measure the pressure within the tissue and to use this measurement to control the suction applied to the tissue through the tubes.
A variety of references describe the placement and use of semipermeable membranes within the body. See, for instance, Mishra (U.S. Pat. No. 5,441,481) which describes a microdialysis probe arranged to have a primary (e.g., electrical) probe secured to it to enable both the microdialysis and primary probe to be extended as a unit for selective sampling and/or administration of compounds to the body. The microdialysis probes are quite large, said to be on the order of 3-4 mm in diameter. Although the reference makes passing reference of the possible “therapeutic application” of their probe, e.g., at column 9, lines 6-20, the suggested delivery of a viscous dextran solution would seem to require the application of tremendous pressures. Moreover, the passage of water through the semipermeable membrane is taught as occurring via chemical (osmotic) means, as compared to water passage brought about by mechanical means, as the result of hydrostatic forces.
Applicant has also previously described methods and related systems for use in site specific therapy of a tissue site. See issued U.S. Pat. No. 6,030,358 and published PCT application No. PCT/US98/16416, the disclosures of which are incorporated herein by reference. In one embodiment, the PCT application provides a system that comprises one or more catheters adapted to be positioned within the tissue site and a delivery/recovery mechanism for employing the catheter(s) to control the movement of bulk fluids and/or active fluid components within or between tissue portions or adjacent tissues in a manner that achieves a therapeutic effect. The catheter(s), in turn, can comprise one or more semipermeable microcatheters, adapted to effect the movement of fluid or fluid components within the tissue site by microdialysis within the tissue site. In its various embodiments, the system previously described by Applicant can be used for the treatment of a variety of disorders, including cerebral edema and compartment syndrome.
In yet another embodiment, Applicant's PCT application describes an apparatus for performing site specific therapy in the event of cerebral edema, the apparatus comprising one or more catheters, each comprising one or more semipermeable membranes, adapted to be positioned in the parenchymal portion of the brain, and adapted to be flowably connected to a source of negative pressure sufficient to remove fluid from the brain in order to alleviate intracranial pressure.
While the embodiments of Applicant's US patent and PCT application remain viable, and valuable, options for various applications, it has become clear that continued efforts, and alternative approaches, are in order with respect to the treatment of tissue swelling, and particularly cerebral edema, as well as compartment syndrome.
Congestive Heart Failure
Congestive heart failure (CHF) provides yet another example of tissue swelling, and particularly nonlocalized tissue swelling. CHF involves the diminished capacity of the heart to circulate blood as a result of injury. The low blood pressure triggers mechanisms to retain body water causing fluid overload or tissue swelling. If CHF is severe, blood flow to the kidneys is restricted such that renal function is impaired without treatment. Over 5 million US patients have CHF with 500,000 newly diagnosed patients each year. Diuretic drugs are currently the primary treatment for CHF patients, but many patients become resistant to further diuretic drug therapy. This resistance leads to fluid overload and a diminished quality of life. Severe fluid overload often leads to hospitalization and more intensive medical therapy. There are about 1 million CHF related hospitalizations each year, typically lasting 4 days, costing an average of $15,000 per hospitalization for a total annual cost of $15 billion.
In addition to the tissue swelling that occurs during CHF, the failing heart is not able to maintain perfusion to vital organs. The body senses low perfusion as a loss of blood volume, and initiates mechanisms designed to retain body water. Sodium is retained as one method to prevent renal excretion of water. Overall, more water than sodium is retained, and hence, serum sodium concentrations are typically low. This, in turn, stimulates additional measures to retain sodium. With increasing water and sodium retention, the venous system becomes overfilled, resulting in an increase in interstitial fluid, and the resulting clinical symptoms of CHF. Excess interstitial fluid results in pulmonary edema, pitting edema of the lower limbs, sacral edema, and ascites. Failure to respond to medicines completes the clinical picture of refractory CHF. These patients must be admitted to the hospital for treatment.
CHF patients often present with low sodium, low potassium, and low magnesium levels. Patients who are hospitalized with chronic CHF have a 32-40% incidence of serum sodium less than 135 mmol/l. Low sodium levels are a problem for several reasons, including:
1) Poor response to drug treatment. Loop diuretics require sodium to be effective. Patients with low sodium become refractory to medical treatment and require hospitalization.
2) Longer length of stay.
3) Increased risk of inpatient death.
4) Increased risk of mortality after discharge.
Several new therapies have emerged to manage late stage CHF, particularly in patients that have become refractory to diuretic drug therapy. These new therapies include hemofiltration, ventricular assist devices, and sophisticated combination drug therapies. These therapies, including hemofiltration, have not only been shown to treat fluid overload, but have also demonstrated the potential reversibility of CHF. None of the emerging therapies address the problem of hyponatremia (low sodium) however, and some can actually tend to aggravate the problem.
Efforts to employ ultrafiltration technology in CHF, to date, have focused on using hemofiltration-like systems to treat CHF fluid overload. Such systems, like conventional hemofiltration used to treat renal failure (kidney dialysis therapy), can remove up to 4 liters in an 8-hour period. The ultrafiltrate is removed from the blood, which results in decreased blood volume and subsequent refilling of plasma fluid from the interstitial space. With ultrafiltration, only molecules less than the molecular weight cutoff of the membrane (generally about 50,000 Daltons) are removed with the water component of the blood. Since most proteins are not removed, ultrafiltration tends to cause a slight increase in colloid osmotic pressure, which can aid refilling of the intravascular space.
Ultrafiltration does not, however, improve serum sodium levels. To the contrary, small molecules such as salts will be quite easily removed with the ultrafiltrate. Furthermore, ultrafiltration alone does not increase renal excretion of sodium, and studies have shown a reduction in urinary sodium levels after ultrafiltration. Ultrafiltration reduces intravascular volume, which can stimulate the renin-angiotensin system. Renin-angiotensin results in retention of sodium and water and is counterproductive to the intention of ultrafiltration.
One author stressed the importance of a negative sodium balance in treatment of CHF (Haller 2000) While total body sodium is elevated in CHF, the neurohumeral axis responds to serum levels. Increasing serum levels will result in normalization of sodium excretion mechanisms, and, ultimately, urinary excretion of sodium. Others have actually given small boluses of hypertonic saline with diuretics and have found increased responsiveness to CHF treatment. (Forssell et al. 1980, Paterna et al. 2000). Yet another group has found that administration of an osmotic agent improved salt excretion. In a single case report of treatment of refractory CHF, urea was given. This resulted in increased salt excretion, increased diuresis, reduced body weight, and corrected sodium deficit (120 mmol/l to 136 mmol/l). (Cauchie et al. 1987) Thus osmotic gradients that favor mobilization of body sodium into the vascular space and thereby elevating serum sodium may be important for normalization of the neurohumeral axis.
Based on published results to date, it would appear that ultrafiltration must be used to treat CHF in combination with other means, typically drugs, to achieve the intended benefit. For instance, only those patients using ACE-inhibitors (which block the renin-angiotensin system) saw urinary excretion of sodium and continued reduction of body water. Guazzi et al. (1994) saw an increase in sodium urinary excretion after ultrafiltration, but one third of their patients had been on ACE-inhibitors, and all were on diuretics. Guazzi et al. concluded that ultrafiltration “may interrupt a positive feedback loop between salt and water retention and activation of the neurohumeral axis.” Agostoni et al. (2000), noting weight loss four days after ultrafiltration (5.8 kg) was greater than the weight of fluid removed during ultrafiltration (3.9 kg), agree that restoring diuresis and response to diuretics is a key factor in treatment of CHF with ultrafiltration (most (22 of 28) of their patients were also on ACE-inhibitors). Even with pharmacological treatment, however, it appears that hyponatremia persists.
A company known as CHF Solutions is a leading advocate of the hemofiltration approach, and focuses on using hemofiltration to treat CHF fluid overload, removing 2 to 4 liters in a 4 to 8 hour period. Their system is very much like conventional hemofiltration used to treat renal failure (kidney dialysis therapy), though it is designed to avoid the use of anti-coagulants. The reusable equipment portion of the system costs about $10,000 per patient station and the disposables sell for $1,000 per patient. See, for example, published International Patent Applications Nos. WO 02/36068, WO 02/47609 and WO 02/053098, assigned to CHF Solutions, Inc., the disclosures of which are incorporated herein by reference. While the CHF Solutions technology may provide desirable attributes, it appears to be neither intended nor designed to address corresponding hyponatremia.
Finally, it can be seen that refractory CHF patients have the following features: 1) low serum sodium concentrations, 2) excess total body water, 3) excess total body sodium, 4) low blood pressure, and 5) non-responsive to medical treatment.
It would therefore be highly desirable to have a treatment regimen that could result in: 1) normalization of serum sodium concentrations to turn off signals to retain sodium, 2) increased urinary excretion of sodium after normalization of inappropriate neurohumeral signals to retain sodium, 3) a net loss of body water, primarily from the interstitial space, and 4) avoidance of excessive intravascular volume loss that can aggravate low blood pressure.